This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. (A) OBJECTIVES Retinal degeneration is a major genetic and age related cause of serious eye disease and blindness. Understanding the molecular interactions of natural and synthetic agonists and antagonists with the visual pigments can provide a new route to halting and possibly reversing such degeneration. This collaboration will utilize grid-enabled AutoLigand and AutoDock, as well as AutoDockTools to computationally, 1) characterize the ligand binding sites of the human rod and cone opsin proteins. 2) predict the binding modes and free energies of known agonists and inverse agonists and 3) explore new inverse agonists using AutoDock Tools interactive Autoligand enhanced interface to help design ligands with increased potency and specificity. The efficacy of the new inverse agonists will be validated using biochemical studies with the human opsin proteins to demonstrate protein ligand interactions.